Angiotensinogen gene silencing predicts bevacizumab response in recurrent glioblastoma patients

Thomas Urup, Linn Gillberg, Signe Regner Michaelsen, Ib Jarle Christensen, Helle Broholm, Ulrik Lassen, Kirsten Grønbæk, Hans Skovgaard Poulsen

Abstract

Background
Bevacizumab in combination with chemotherapy has shown activity in recurrent glioblastoma patients. Patients who achieve response to bevacizumab have improved survival as well as quality of life. Recently, we found that low gene expression of angiotensinogen (AGT) was a predictive factor for bevacizumab response in recurrent glioblastoma patients. Promoter methylation of AGT has been associated with AGT gene silencing. This study investigated if AGT promoter methylation in tumor tissue predicts response to bevacizumab combination therapy in recurrent glioblastoma patients.
Methods
The study included 82 recurrent glioblastoma patients treated with bevacizumab combination therapy whom were both RANO response and biomarker evaluable. DNA methylation of 7 CpG sites in the AGT promoter was measured using pyrosequencing. AGT gene expression in tumor tissue was measured by NanoString analysis.
For each CpG site, methylation was associated with angiotensinogen gene expression using Spearman correlations and to treatment response using Mann-Whitney U test and logistic regression analysis.
Results
Preliminary results on 58 of 82 patients analyzed: AGT promoter methylation was inversely associated with AGT gene expression on Position 1 (P=0.049) and borderline significant on Position 2 (P=0.074). Compared to non-responding patients, responders expressed significantly higher methylation levels of Position 1 (P=0.015), 2 (P=0.013) and 3 (P=0.045). Position 4-7 were not associated with AGT gene expression or response. By univariate analysis, increased methylation of the AGT promoter region were predictive for bevacizumab response on Position 1 (2-fold increase: OR=1.81; 95%CI: 1.02-3.23; P=0.043) and on Position 2 (2-fold increase: OR=2.08; 95%CI: 1.04-4.17; P=0.040).
Conclusion
Increased methylation of two AGT promoter regions is associated with AGT gene silencing and is predictive for bevacizumab response in recurrent glioblastoma patients. If validated, this method can be used to identify patients who will or will not benefit from bevacizumab combination therapy.
Updated results will be presented.
OriginalsprogEngelsk
Publikationsdato2018
DOI
StatusUdgivet - 2018
BegivenhedASCO 2018 - Chicago
Varighed: 1 jun. 20185 jun. 2018

Konference

KonferenceASCO 2018
ByChicago
Periode01/06/201805/06/2018

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